Daily Ards Research Analysis

BACKGROUND: Diaphragm dysfunction impedes weaning from mechanical ventilation. Transvenous diaphragm neurostimulation can increase diaphragm strength but its impact on patient outcomes is uncertain. METHODS: This international, multicenter, open-label, randomized clinical trial (RESCUE-3) included adult patients requiring mechanical ventilation for ≥96 hours who met readiness-to-wean criteria and failed ≥2 weaning attempts. Patients were randomized to twice-daily transvenous diaphragm neurostimulation (Treatment) or standard of care (Control). The primary outcome was successful weaning at Day 30. Secondary outcomes included duration of ventilation to Day 30 and mortality at Day 30. The pre-specified primary analysis utilized a Bayesian approach with borrowing of prior information from a previous phase II randomized trial, downweighted to account for possible differences in trials. RESULTS: Due to slow enrolment and financial considerations, the trial was halted at the first interim analysis after 200 patients were randomized. Overall, 216 patients were randomized in the modified intent-to-treat population (Treatment, 102; Control 114). At Day 30, 71 (70%) Treatment patients and 69 (61%) Control patients were successfully weaned (adjusted hazard ratio 1.34, 95% credible interval 1.01-1.78, posterior probability of superiority, 97.9%). Treatment reduced the duration of ventilation (adjusted difference -2.5 days, 95% credible interval -5.0 to 0.1, posterior probability of superiority, 97.1%). Serious adverse events were reported in 36% of Treatment patients and 24% of Control patients; 9.8% of Treatment patients and 10.5% of Control patients died (adjusted hazard ratio 0.74, 95% credible interval 0.37-1.46, posterior probability of superiority 80.6%). CONCLUSION: Although the trial was stopped early due to slow enrollment, transvenous diaphragm neurostimulation showed a high probability of potential benefit for weaning success but with a possible increase in serious adverse events. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03783884.

BACKGROUND: Refractory acute respiratory distress syndrome (ARDS) is the leading cause of death in patients with Covid-19. Large studies of lung pathology in patients who died of Covid-19-ARDS may help to understand the mechanisms of death and to guide further research. METHODS: This prospective multicentre cohort study included 338 post-mortem, percutaneous, lung biopsies from 169 patients who died of Covid-19-ARDS between 22/04/2020 and 08/03/2021 in 26 intensive care units in France. The biopsies were done at the bedside by the intensivist immediately after death, using a 14G needle and following anatomical landmarks. A pathologist examined all biopsies, describing all elementary lesions and establishing a final histopathological diagnosis. RESULTS: Lung parenchyma was evaluable in 155/169 (92%) patients. Early, proliferative-phase diffuse alveolar damage (DAD) was the most common finding (39%), followed by late proliferative-phase DAD (32%) and exudative-phase DAD (18%); fibrotic-phase DAD was present in three (2%) patients. Organising pneumonia (OP) and acute fibrinous and organising pneumonia (AFOP) were evidenced in 21 (13%) and 16 (9%) patients, respectively. Unclassified interstitial lesions were seen in 33 (21%) patients. Microthrombi were uncommon (6%). CONCLUSIONS: DAD was the most common pathological pattern, whereas collagen fibrosis and microthrombi were rare. A quarter of patients had evidence of OP or AFOP. This substantial prevalence of corticosteroid-sensitive patterns suggests that selected patients with refractory Covid-19-ARDS might benefit from higher doses or longer courses of corticosteroids. CLINICALTRIALS: gov NCT04675281. Registered 19 December 2020.

The transient receptor potential cation channel subfamily member 6 (TRPC6) represents an emerging druggable target with a broad therapeutic spectrum. TRPC6 Inhibitors are currently investigated for focal segmental glomerulosclerosis (FSGS), acute respiratory distress syndrome due to COVID-19, and pulmonary hypertension. In the cardiovascular system, there is evidence that TRPC6 is critically involved in the development of cardiac hypertrophy, arrhythmia susceptibility and risk of restenosis after coronary stent implantation. However, data on systemic effects of TRPC6 modulation remain scarce. To assess the phenotypic consequences of inhibiting TRPC6 in different organ systems, we explored public databases to identify single nucleotide polymorphisms (SNPs) that are associated with TRPC6 expression in different tissues. A phenome-wide association study was then performed in 475,739 individuals of UK Biobank to associate genetically-mediated reduced TRPC6 expression with 64 phenotypes in nine organ/disease categories. Lower TRPC6 expression was nominally associated with reduced risk of anxiety, heart failure, and stroke, as well as an increased risk of venous thromboembolism, hypertension, appendicitis and liver cirrhosis. After correction for multiple testing, lower TRPC6 expression remained significantly associated with reduced risk of coronary artery disease and atrial fibrillation. Notably, no deleterious phenotypes were observed, suggesting a favorable profile of systemic TRPC6 inhibition. While these findings indicate potential therapeutic benefits, nominally associated phenotypes, however, mandate careful clinical investigation and provide a basis for further experimental exploration.